Systems and methods for selective, targeted opening of the blood-brain barrier

ABSTRACT

Systems and methods for applying ultrasound sonication to temporarily disrupt a patient&#39;s blood-brain barrier (BBB) include storing threshold values of an acoustic response level, an acoustic response dose and a tissue response dose associated with a target BBB region and its surrounding regions based on anatomical characteristics thereof; causing the ultrasound transducer to transmit one or more pulses/waves; measuring the acoustic response level, the acoustic response dose, and/or the tissue response dose associated with the target BBB region and/or its surrounding regions; comparing the measurement with a corresponding stored threshold value; and operating the transducer based at least in part on the comparison.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to, and the benefit of, U.S.Provisional Patent Application No. 62/510,023, filed on May 23, 2017,the entire disclosure of which is hereby incorporated by reference.

FIELD OF THE INVENTION

The field of the invention relates generally to ultrasound systems and,more particularly, to systems and methods for selective, targetedopening of the blood-brain barrier using an ultrasound procedure.

BACKGROUND

The blood-brain barrier (BBB), formed by layers of cells in the centralnervous system (CNS), excludes large molecules from entering the brainparenchyma, thereby protecting it from damage by toxic foreignsubstances. But the BBB also presents one of the largest obstacles totreating many brain diseases. Specifically, the BBB prevents manytherapeutic agents, such as drugs and gene-therapy vectors, fromreaching a patient's brain tissue. For example, treatments for CNSinfections, neurodegenerative diseases, congenital enzyme defects andbrain cancer are all hampered by the ability of the BBB to block passageof, inter alia, antibiotics, anti-retroviral drugs, enzyme replacementtherapy, gene preparations and anti-neoplastic drugs. It is thusdesirable to temporarily and locally “open” the BBB to permittherapeutic quantities of these agents to access the affected braintissue.

Focused ultrasound (i.e., acoustic waves having a frequency greater thanabout 20 kiloHertz) has been utilized to open the BBB in the treatmentof neurological diseases. The mechanistic event underlying the BBBopening appears to involve the reaction of microbubbles to ultrasonicpulses, which can result in an array of behaviors known as acousticcavitation. In stable cavitation, microbubbles expand and contract withthe acoustic pressure rarefaction and compression over several cycles;such action can result in dilation and contraction of blood vessels inthe vicinity. In inertial cavitation, the microbubbles can expand toseveral factors greater than their equilibrium radius and subsequentlycollapse due to the inertia of the surrounding tissue. In both cases,the consequent disruption of blood vessels induces “opening” of the BBB.

An uncontrolled microbubble cavitation, however, may result in undesireddamage to and around the BBB. For example, ablating cells formingportions of the BBB may not only compromise BBB function but also causeunwanted cell death or necrosis in surrounding tissue. To minimize theundesired effects of microbubble cavitation during BBB disruption, oneconventional approach utilizes a passive cavitation detector thatmeasures the acoustic response of the microbubbles after each ultrasoundsonication; if the acoustic response level is above a predefinedthreshold amplitude, the ultrasound procedure is suspended. The effectsof microbubble cavitation, however, may be cumulative along a sonicationand over a series of sonications, and may also depend on the propertiesof the tissue where cavitation occurs—that is, measuring the acousticresponse from the microbubbles may not accurately reflect the effect ofcavitation on the surrounding tissue.

Accordingly, there is a need to reliably detect microbubble cavitationresulting from ultrasound waves and monitor effects of the cavitation onthe local tissue in real time so as to avoid permanent damage to the BBBor its surrounding tissue.

SUMMARY

The present invention provides systems and methods for inducingmicrobubble cavitation with ultrasound in order to disrupt a target BBBregion in a controlled and reversible manner. The formation andcumulative amount of microbubble cavitation may be reliably detectedusing (i) an acoustic response level that represents a temporal acousticeffect of the microbubbles after each ultrasound sonication pulse and(ii) an acoustic response dose that represents a cumulative effect ofthe microbubbles over a single sonication or multiple sonications. Forexample, the acoustic response dose may be an integral of thetime-varying acoustic response level over a predetermined time period.Therefore, if the detected acoustic response level and/or cumulativeacoustic response dose exceeds a predetermined threshold reflecting anupper limit on the magnitude and/or cumulative amount of microbubblecavitation that can clinically tolerated—e.g., that does not permanentlyaffect or damage the target BBB region or its surrounding tissue—theultrasound procedure may be suspended to avoid further inducingmicrobubble cavitation. If, however, the detected acoustic responselevel and/or cumulative acoustic response dose is below thepredetermined threshold, additional microbubble cavitation may beinduced to further disrupt the target BBB region. This may be achievedby operating the ultrasound transducer to deliver additional acousticenergy to the target BBB region and/or activating a microbubbleadministration system to introduce additional microbubbles.

In some embodiments, an imaging device (e.g., a magnetic resonanceimaging (MRI) device) is employed to characterize tissue types and/orproperties of the target BBB region and/or its surrounding tissue; eachtype and location of tissue, depending on its properties, may havecorresponding tolerances for the acoustic response level and acousticresponse dose. In addition, the imaging device may measure thecavitation effects (e.g., a temperature increase or an area that isdisrupted) on the target BBB region and/or the surrounding tissue inreal time. If an undesired effect on the target BBB region and/or itssurrounding tissue is observed (e.g., the temperature increase exceedinga threshold and/or a disrupted area larger than a desired size), theultrasound procedure may be halted. Accordingly, approaches described inthe current invention may advantageously avoid permanent damage of thetarget BBB region and its surrounding tissue by reliably detectingmicrobubble cavitation events and monitoring effects of the cavitationon the target and/or surrounding tissue in real time.

Accordingly, in a first aspect, the invention pertains to a system fortemporarily disrupting a patient's blood-brain barrier (BBB). In variousembodiments, the system includes an ultrasound transducer and acontroller configured to (a) store one or more threshold values of anacoustic response level, a cumulative acoustic response dose and/or atissue response dose associated with one or more target BBB regions andtheir surrounding regions; (b) cause the transducer to transmit one ormore ultrasound pulses; (c) acquire the acoustic response level, theacoustic response dose, and/or the tissue response dose associated withthe target BBB region(s) and/or the surrounding regions; (d) compare themeasurement with a corresponding stored threshold value; and (e) operatethe transducer based at least in part on the comparison. In oneimplementation, the controller is configured to operate the transducerby adjusting a transmitting power and/or a sonication pattern associatedwith the transducer. In addition, the controller may be furtherconfigured to compute the acoustic response dose by integrating theacoustic response level over a predetermined time period.

In some embodiments, the controller is further configured to cause adetection device and/or the transducer to measure acoustic signals fromthe target BBB region(s) and/or the surrounding regions; and determinethe acoustic response level, the acoustic response dose, and/or thetissue response dose based at least in part on the measured acousticsignals. In addition, the system may further include one or more filtersfor filtering the measured acoustic signals from the target BBBregion(s) and/or the surrounding regions. The filter(s) may beconfigured to select a harmonic and/or a sub-harmonic response to thetransmitted ultrasound pulse. Alternatively, the filter(s) may beconfigured to select a broadband response to the transmitted ultrasoundpulse.

In one embodiment, the controller is further configured to causegeneration of microbubbles in the target BBB region(s) and/or thesurrounding regions using the transducer. Additionally or alternatively,the system may include an administration device for introducingmicrobubbles into the target BBB region(s) and/or the surroundingregions. In one implementation, the administration device introduces aseed microbubble into the target BBB region(s) and/or the surroundingregions; the controller is then configured to cause generation ofadditional microbubbles using the seed microbubble and the transducer.

In various embodiments, the controller is further configured todetermine the threshold values of the acoustic response level, thecumulative acoustic response dose and/or the tissue response doseassociated with the target BBB region(s) and/or the surrounding regionsbased at least in part on anatomical characteristics thereof. In oneembodiment, the system includes an imaging device for acquiring theanatomical characteristics of the target BBB region and its surroundingregions. For example, the image device may acquire images of the targetBBB region(s) and/or the surrounding regions; the controller is furtherconfigured to determine the tissue response dose based at least in parton the acquired images.

There may be multiple target BBB regions and the controller may befurther configured to determine and store the threshold values of theacoustic response level, the cumulative acoustic response dose and/orthe tissue response dose associated with each of the target BBB regionsand each of their surrounding regions. In some embodiments, thethreshold values of the acoustic response level, the cumulative acousticresponse dose and/or the tissue response dose associated with the targetBBB region(s) are different from the threshold values of the acousticresponse level, the cumulative acoustic response dose and/or the tissueresponse dose associated with the surrounding regions. In addition, thesurrounding regions may include tissue having different types atdifferent locations; the controller may be further configured todetermine the threshold values of the acoustic response level, thecumulative acoustic response dose and/or the tissue response doseassociated with each type of the tissue at each location of thesurrounding regions.

The tissue response dose may include a temperature associated with thetarget BBB region(s) and/or the surrounding regions. In someembodiments, the tissue response dose is acquired by measuring an MRI T₂relaxation time associated with the target BBB region(s) and/or thesurrounding regions. In addition, the tissue response dose may includeinformation derived from MRI T₂* imaging and/or MRI T₂* weighted imagingassociated with the target BBB region(s) and/or the surrounding regions.Further, the controller may be configured to determine whether theacoustic response level, the acoustic response dose, and/or the tissueresponse dose exceeds the corresponding threshold value; and if so,suspend ultrasound sonication, and if not, cause the transducer totransmit a second ultrasound pulse.

In another aspect, the invention relates to a method of applyingultrasound sonication from a transducer to temporarily disrupt apatient's BBB. In various embodiments, the method includes (a) storingone or more threshold values of an acoustic response level, an acousticresponse dose and/or a tissue response dose associated with one or moretarget BBB regions and their surrounding regions based on anatomicalcharacteristics thereof; (b) causing the transducer to transmit one ormore ultrasound pulses; (c) acquiring the acoustic response level, theacoustic response dose, and/or the tissue response dose associated withthe target BBB region(s) and/or the surrounding regions; (d) comparingthe measurement with a corresponding stored threshold value; and (e)operating the transducer based at least in part on the comparison. Forexample, operating the transducer may include adjusting a transmissionpower and/or a pulse pattern associated with the transducer. In oneimplementation, the acoustic response dose includes an integral of theacoustic response level over a predetermined time period.

In some embodiments, the method further includes measuring acousticsignals from the target BBB region(s) and/or the surrounding regions;and determining the acoustic response level, the acoustic response dose,and/or the tissue response dose based at least in part on the measuredacoustic signals. In addition, the method may include filtering themeasured acoustic signals using one or more filters. For example, thefilter(s) may select a harmonic and/or a sub-harmonic response to thetransmitted ultrasound pulse. Alternatively, the filter(s) may select abroadband response to the transmitted ultrasound pulse.

In some embodiments, the method further includes introducingmicrobubbles into the target BBB region(s) and/or the surroundingregions. The microbubbles may be introduced by activating the transducerto transmit the second pulse and/or using an administration device. Inone embodiment, the administration device injects a seed microbubbleinto the target BBB region(s) and/or its surrounding regions, and themicrobubbles are generated using the seed microbubble and thetransducer.

In various embodiments, the threshold values of the acoustic responselevel, the cumulative acoustic response dose and/or the tissue responsedose associated with the target BBB region(s) and the surroundingregions are determined based at least in part on anatomicalcharacteristics thereof. In one embodiment, the method further includesacquiring images of the target BBB region(s) and/or the surroundingregions; the anatomical characteristics are then determined based atleast in part on the acquired images.

There may be multiple target BBB regions; the method may further includedetermining and storing the threshold values of the acoustic responselevel, the cumulative acoustic response dose and/or the tissue responsedose associated with each of the target BBB regions and each of theirsurrounding regions. In addition, the threshold values of the acousticresponse level, the cumulative acoustic response dose and/or the tissueresponse dose associated with the target BBB region may be differentfrom the threshold values of the acoustic response level, the cumulativeacoustic response dose and/or the tissue response dose associated withthe surrounding regions. In some embodiments, the surrounding regionsinclude tissue having different types at different locations; the methodfurther includes determining the threshold values of the acousticresponse level, the cumulative acoustic response dose and/or the tissueresponse dose associated with each type and/or each location of thetissue in the surrounding regions.

The tissue response dose may include a temperature associated with thetarget BBB region(s) and the surrounding regions. In some embodiments,the tissue response dose is acquired by measuring an MRI T₂ relaxationtime associated with the target BBB region(s) and/or the surroundingregions. In addition, the tissue response dose may include informationderived from MRI T₂* imaging and/or MRI T₂* weighted imaging associatedwith the target BBB region(s) or the surrounding regions. In oneembodiment, the method further includes determining whether the acousticresponse level, the acoustic response dose, and/or the tissue responsedose exceeds the corresponding threshold value; and if so, suspendingthe ultrasound sonication, and if not, causing the transducer totransmit a second ultrasound pulse.

Still another aspect of the invention relates to a method of applying atherapeutic agent to a brain tumor. In various embodiments, the methodincludes (a) storing one or more threshold values of an acousticresponse level, an acoustic response dose and/or a tissue response doseassociated with one or more target BBB regions and/or their surroundingregions based on anatomical characteristics thereof; (b) transmitting,using a phased array of transducers, one or more ultrasound pulsesconverging at a focus that includes the target BBB regions; (c)acquiring the acoustic response level, the acoustic response dose,and/or the tissue response dose associated with the target BBB region(s)or their surrounding regions; (d) comparing the measurement with acorresponding stored threshold value; (e) operating the transducer arraybased at least in part on the comparison; and (f) administering thetherapeutic agent to the target BBB region. The therapeutic agent mayinclude Busulfan, Thiotepa, CCNU (lomustine), BCNU (carmustine), ACNU(nimustine), Temozolomide, Methotrexate, Topotecan, Cisplatin,Etoposide, Irinotecan/SN-38, Carboplatin, Doxorubicin, Vinblastine,Vincristine, Procarbazine, Paclitaxel, Fotemustine,Ifosfamide/4-Hydroxyifosfamide/aldoifosfamide, Bevacizumab,5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel, and/or Cytarabine(cytosine arabinoside, ara-C)/ara-U.

As used herein, the term “substantially” means±10 seconds, and in someembodiments, ±5 seconds. “Clinically tolerable” means having anundesired (and sometimes the lack of a desired) effect on tissue that isconsidered insignificant by clinicians, e.g., prior to triggering theonset of damage thereto. Reference throughout this specification to “oneexample,” “an example,” “one embodiment,” or “an embodiment” means thata particular feature, structure, or characteristic described inconnection with the example is included in at least one example of thepresent technology. Thus, the occurrences of the phrases “in oneexample,” “in an example,” “one embodiment,” or “an embodiment” invarious places throughout this specification are not necessarily allreferring to the same example. Furthermore, the particular features,structures, routines, steps, or characteristics may be combined in anysuitable manner in one or more examples of the technology. The headingsprovided herein are for convenience only and are not intended to limitor interpret the scope or meaning of the claimed technology.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing will be more readily understood from the followingdetailed description of the invention in conjunction with the drawings,wherein:

FIG. 1 schematically depicts an exemplary ultrasound system inaccordance with various embodiments of the current invention;

FIG. 2A depicts presence of microbubbles in a target tissue region inaccordance with various embodiments;

FIGS. 2B-2D depict various configurations of the transducer elementsperforming a cavitation-detecting approach in accordance with variousembodiments;

FIGS. 3A and 3B depict various relationships between an amplitude of adetected acoustic response level and a magnitude of the microbubblecavitation in accordance with various embodiments;

FIG. 3C depicts an exemplary relationship between a temporal acousticresponse level and a cumulative acoustic response dose in accordancewith various embodiments;

FIGS. 4A-4C illustrate amplitude variations of ultrasound pulses duringan ultrasound procedure in accordance with various embodiments;

FIGS. 4D-4F illustrate various sonication patterns applied during anultrasound procedure in accordance with various embodiments;

FIG. 5A depicts a relationship between a tissue response dose and adetected acoustic response level in accordance with various embodiments;

FIG. 5B depicts a relationship between a tissue response dose and a sizeof the target/non-target region disrupted by the microbubble cavitationin accordance with various embodiments;

FIG. 6 is a flow chart illustrating an approach of using ultrasoundsonication and microbubbles to temporarily disrupt a patient's BBB inaccordance with some embodiments of the present invention.

DETAILED DESCRIPTION

FIG. 1 illustrates an exemplary ultrasound system 100 for focusingultrasound within a patient's brain (e.g., a target BBB region) throughthe skull. The applied ultrasound sonication may induce microbubblecavitation and disrupt the target BBB region in a controlled andreversible manner. In various embodiments, the system 100 includes aphased array 102 of transducer elements 104, a beamformer 106 drivingthe phased array 102, a controller 108 in communication with thebeamformer 106, and a frequency generator 110 providing an inputelectronic signal to the beamformer 106. In various embodiments, thesystem further includes an imager 112, such as a magnetic resonanceimaging (MRI) device, a computer tomography (CT) device, a positronemission tomography (PET) device, a single-photon emission computedtomography (SPECT) device, or an ultrasonography device, for determininganatomical characteristics of the skull, the target BBB region and thetissue surrounding the BBB region. The ultrasound system 100 and/orimager 112 may be utilized to detect the presence, type, and/or locationassociated with microbubble cavitation as further described below.Additionally or alternatively, in some embodiments, the system furtherincludes a cavitation detection device (such as a hydrophone or suitablealternative) 114 to detect information associated with microbubblecavitation.

The array 102 may have a curved (e.g., spherical or parabolic) shapesuitable for placing it on the surface of the skull, or may include oneor more planar or otherwise shaped sections. Its dimensions may varybetween millimeters and tens of centimeters. The transducer elements 104of the array 102 may be piezoelectric ceramic elements, and may bemounted in silicone rubber or any other material suitable for dampingthe mechanical coupling between the elements 104. Piezo-compositematerials, or generally any materials capable of converting electricalenergy to acoustic energy, may also be used. To assure maximum powertransfer to the transducer elements 104, the elements 104 may beconfigured for electrical resonance at 50 Ω, matching input connectorimpedance.

The transducer array 102 is coupled to the beamformer 106, which drivesthe individual transducer elements 104 so that they collectively producea focused ultrasonic beam or field. For n transducer elements, thebeamformer 106 may contain n driver circuits, each including orconsisting of an amplifier 118 and a phase delay circuit 120; each drivecircuit drives one of the transducer elements 104. The beamformer 106receives a radio frequency (RF) input signal, typically in the rangefrom 0.1 MHz to 1.0 MHz, from the frequency generator 110, which may,for example, be a Model DS345 generator available from Stanford ResearchSystems. The input signal may be split into n channels for the namplifiers 118 and delay circuits 120 of the beamformer 106. In someembodiments, the frequency generator 110 is integrated with thebeamformer 106. The radio frequency generator 110 and the beamformer 106are configured to drive the individual transducer elements 104 of thetransducer array 102 at the same frequency, but at different phasesand/or different amplitudes.

The amplification or attenuation factors al-an and the phase shiftsal-a, imposed by the beamformer 106 serve to transmit and focusultrasonic energy through the patient's skull onto a selected region 122of the patient's BBB, and account for wave distortions induced in theskull and soft brain tissue. The amplification factors and phase shiftsare computed using the controller 108, which may provide thecomputational functions through software, hardware, firmware,hardwiring, or any combination thereof. For example, the controller 108may utilize a general-purpose or special-purpose digital data processorprogrammed with software in a conventional manner, and without undueexperimentation, in order to determine the phase shifts andamplification factors necessary to obtain a desired focus or any otherdesired spatial field patterns. In certain embodiments, the computationis based on detailed information about the characteristics (e.g.,structure, thickness, density, etc.) of the intervening tissue (e.g.,the skull and/or brain tissue) located between the transducer elementsand the selected region 122 and their effects on propagation of acousticenergy. Such information may be obtained from the imager 112. Imageacquisition may be three-dimensional or, alternatively, the imager 112may provide a set of two-dimensional images suitable for reconstructinga three-dimensional image of the skull from which thicknesses anddensities can be inferred. Image-manipulation functionality may beimplemented in the imager 112, in the controller 108, or in a separatedevice.

Referring to FIG. 2A, in various embodiments, the acoustic energyemitted by the transducer elements 104 may be above a threshold andthereby cause generation of a small cloud of gas bubbles (or“microbubbles”) 202 in the liquid contained in the target BBB region204. The microbubbles 202 can be formed due to the negative pressureproduced by the propagating ultrasonic waves or pulses, when the heatedliquid ruptures and is filled with gas/vapor, or when a mild acousticfield is applied on tissue containing cavitation nuclei. Generally, at arelatively low acoustic power (e.g., 1-2 Watts above themicrobubble-generation threshold), however, the generated microbubbles202 undergo oscillation with compression and rarefaction that are equalin magnitude and thus the microbubbles generally remain unruptured. At ahigher acoustic power (e.g., more than 10 Watts above themicrobubble-generation threshold), the generated microbubbles 202undergo rarefaction that is greater than compression, which may causecavitation of the microbubbles. The microbubble cavitation may result intransient disruption (or “opening”) of the targeted BBB region 204,thereby allowing therapeutic or prophylactic agents present in thebloodstream to penetrate the “opened” BBB region 204 and effectivelydeliver therapy to the targeted brain cells.

Referring again to FIG. 1, in some embodiments, microbubbles areintroduced into the patient's bloodstream, and may either be injectedsystemically into the patient's brain or locally into the target BBBregion 204 using an administration system 124. For example, themicrobubbles may be introduced into the patient's brain in the form ofliquid droplets that subsequently vaporize, as gas-filled bubbles, orentrained with another suitable substance, such as a conventionalultrasound contrast agent. The injected microbubbles may themselvescreate or facilitate the creation of additional microbubbles. Therefore,the actual effect on the tissue may result from a combination of theinjected microbubbles and microbubbles additionally created in thetissue. Approaches to generating the microbubbles and/or introducing themicrobubbles to the target region are provided, for example, in U.S.Patent Application Nos. and 62/366,200, 62/597,071, Ser. Nos.15/708,214, 15/837,392 and 62/597,073, the contents of which areincorporated herein by reference.

To avoid undesired damage of the target BBB region 204 and/or itssurrounding tissue 206 resulting from the microbubble cavitation, invarious embodiments, the formation and/or amount of induced microbubbles202 in the target BBB region 204 is monitored by detecting acousticsignals emanating therefrom using the cavitation detection device 114,which then transmits the signals to the controller 108. Alternatively,the transducer elements 104 may possess both transmit and detectcapabilities. Referring to FIG. 2B, in one embodiment, each individualtransducer element 104 alternates between transmitting ultrasoundsignals to the microbubbles and receiving ultrasound signals therefrom.For example, all transducer elements 104 may substantiallysimultaneously transmit ultrasound to the microbubbles 202 andsubsequently receive echo signals therefrom. Referring to FIG. 2C, inone implementation, the transducer array is divided into multiplesub-regions 212; each sub-region 212 comprises a one- or two-dimensionalarray (i.e., a row or a matrix) of transducer elements 104. Thesub-regions 212 may be separately controllable, i.e., they are eachcapable of (i) emitting ultrasound waves/pulses at amplitudes,frequencies and/or phases that are independent of the amplitudes and/orphases of the other sub-regions 212, and (ii) measuring acoustic signalsfrom the microbubbles 202. In one embodiment, the sub-regions 212 areassigned different amplitudes, frequencies and/or phases from oneanother, and activated, one at a time, to transmit ultrasound to andreceive echo signals from the microbubbles 202. Referring to FIG. 2D, inanother embodiment, the transducer array is divided into a transmitregion 214 and a receive region 216; transducer elements in the transmitregion 214 transmit the ultrasound waves/pulses while transducerelements in the receive region 216 receive the echo signals from themicrobubbles 202. The received signals are then transmitted to thecontroller 108 for analysis. The transmit region 214 and receive region216 of the transducer array may be configured in different patterns andshapes at various locations of the transducer array.

The microbubble acoustic signals may be emissions resulting from theshape change of the microbubbles 202 and/or reflections resulting fromthe microbubble encapsulating gas. The acoustic signals may include (i)an instantaneous acoustic response level and/or (ii) a spectraldistribution of the acoustic response. The acoustic response levelcorresponds, either linearly or nonlinearly but in a known manner, tothe magnitude of the acoustically driven cavitation. For example,referring to FIG. 3A, the amplitude of the detected acoustic responselevel may linearly correlate to the magnitude of the microbubblecavitation through the entire range thereof. Alternatively, referring toFIG. 3B, the linear correlation may occur only when the magnitude of themicrobubble cavitation is below a threshold cavitation, C_(th). When themagnitude of the cavitation exceeds the threshold, C_(th), a smallincrease of the cavitation may result in a large increase of theresponse level of the acoustic signals.

The relationship between the amplitude of the acoustic response leveland the magnitude of the microbubble cavitation may be empiricallyestablished from a pre-clinical study, a pre-treatment procedure, and/orfrom known literature. For example, in a pre-clinical study, the imager112 may directly image the amount and/or area associated with themicrobubble cavitation events, and based thereon, the magnitude of themicrobubble cavitation may be quantified. Substantially simultaneously,the acoustic signals from the microbubble cavitation can be detected bythe cavitation detection device 114 and/or transducer array 102 andsubsequently analyzed by the controller 108 to acquire the amplitudesassociated therewith. A relationship between the quantified magnitude ofthe microbubble cavitation and the amplitude of the acoustic responselevel can then be established.

In addition, the acoustic signals may include a spectral distribution ofthe acoustic response that indicates the type and/or location of themicrobubble cavitation. This is because each type of the cavitation ateach location may have its own spectral “signature” that represents theunique nonlinear response of the microbubbles. For example, the acousticresponse of microbubbles may be linear at a relatively low acousticpower (e.g., 1-2 Watts above the microbubble-generation threshold); thespectral distribution of the detected signals may thus include afrequency that is the same as or a harmonic of that of the incidentultrasound waves (i.e., the fundamental frequency or a base harmonicfrequency). If stable cavitation is induced at an intermediate acousticpower (e.g., 5 Watts above the microbubble-generation threshold), thespectral distribution of the detected signals may include a strongsub-harmonic response (i.e., having more components at the sub-harmonicfrequencies and/or having larger amplitudes of the sub-harmonicfrequencies). Likewise, if inertial cavitation is induced at a highacoustic power (e.g., 10 Watts above the microbubble-generationthreshold), the detected signals may include a broadband response. Thus,by detecting and analyzing the acoustic signals emitted from themicrobubbles, the presence, type and/or of cavitation induced in tissueduring an ultrasound procedure can be determined. Approaches tomonitoring the cavitation events using signals from the microbubbles areprovided, for example, in U.S. patent application Ser. No. 15/415,351,and the content of which is incorporated herein by reference.

In various embodiments, the detected spectral distribution of theacoustic response is filtered by one or more suitable filtersimplemented in hardware and/or software. For example, the filters mayinclude multiple bandpass filters and/or window functions, eachassociated with a frequency component (e.g., the base harmonic frequencyor sub-harmonic frequency) of the spectral signature. In one embodiment,the filters include a baseband filter that allows the baseband responseof the signals to be processed. The filters may thus advantageouslyimprove the resolution and/or signal-to-noise ratio of the detectedsignals, thereby allowing the presence, type and/or location of themicrobubble cavitation to be reliably and accurately determined.Suitable filters are well-known in the art of signal processing (inparticular, digital signal processing) and readily implemented withoutundue experimentation.

Alternatively or additionally, the microbubble cavitation may bemonitored using a cumulative acoustic response dose value thatcorresponds, either linearly or nonlinearly, to the cumulativecavitation-related acoustic energy delivered via the microbubbles overan entire sonication or over multiple successive sonication pulses. Thisis because the tissue tolerance may be a function both of theinstantaneous response level and the cumulative response dose. Forexample, even if an instantaneous response level is below itscorresponding predetermined threshold, the cumulative response dose mayexceed its predetermined threshold; this may result in permanent effectsor damage to the target BBB region or its surrounding tissue.Conversely, even if the cumulative response dose is below itspredetermined threshold, a burst instantaneous response level above thethreshold may be clinically intolerable. Accordingly, in a preferredembodiment, both the instantaneous response level and cumulativeresponse dose are monitored during the ultrasound procedure.

In some embodiments, the cumulative acoustic response dose is definedutilizing the instantaneous acoustic response level. For example,referring to FIG. 3C, the cumulative acoustic response dose may be anintegral of the acoustic response level over a predetermined timeperiod, Δt; the predetermined time period may be the entire sonicationprocedure or over one or more successive sonication pulses. Accordingly,based on the received acoustic signals during the ultrasound procedure,the controller 108 may compute the acoustic response dose during anydesired time period.

In addition, the detected acoustic response level and/or computedacoustic response dose may be compared with their associatedpredetermined threshold values stored in a databased in memory; thethreshold values represent an upper limit of the magnitude and/or amountof the microbubble cavitation that can be clinically tolerated. If theacoustic response level and/or acoustic response dose is at or above thepredetermined threshold value, the ultrasound procedure may be suspendedto avoid inducing more microbubble cavitation, thereby avoiding damageto the target and/or non-target tissue regions. If, however, theacoustic response level and/or acoustic response dose is below thecorresponding predetermined threshold value, the ultrasound transducerelements 104 may deliver additional acoustic energy to the microbubblesso as to induce additional cavitation to disrupt the target BBB region.For example, referring to FIGS. 4A-4C, the transducer elements 104 maybe activated to transmit one or more additional pulses 402 to themicrobubbles; the amplitude of the additional pulse(s) 402 may be thesame or different from that of the previous pulses 404. Alternatively oradditionally, the sonication pattern (e.g., a frequency, a focusingshape, and/or a sonication profile varying with time) of the additionalpulses 402 may be the same or different from that of the previous pulses404. For example, a duty cycle of the elements' activation time in theadditional pulses 402 may be the same, smaller than or larger than thatin the previous pulses 404 as depicted in FIGS. 4D-4F. Generally, theduty cycles positively correlate to energy levels delivered to themicrobubbles—a higher duty cycle corresponds to larger energy, becausethe power is on for most of the time.

In some embodiments, when the acoustic response level and/or acousticresponse dose is below the corresponding predetermined threshold value,additional microbubbles may be generated and/or introduced into thetarget BBB region in order to induce further microbubble cavitation.This can be achieved by activating the transducer array 102 to delivermore acoustic energy to the target BBB region and/or activating theadministration system 124 to inject additional microbubbles into thetarget BBB region. In some embodiments, the administration device 124first injects a seed microbubble into the target BBB region; thetransducer array 102 then transmits an acoustic energy to the seedmicrobubble so as to generate more microbubbles.

The threshold values of the acoustic response level and cumulativeacoustic response dose may be determined based on the tissue types,properties and/or other anatomical characteristics of the target BBBregion and/or its surrounding region—the target BBB region and/or itssurrounding region may include different types of tissue and/or havedifferent tissue properties (e.g., densities, tolerance of thermalenergy, thermal absorption coefficients, etc.) and thereby responddifferently to the ultrasound pulses and/or microbubble cavitation;consequently, thresholds of the acoustic response level and acousticresponse dose may differ for different types of tissue at differentlocations. In addition, the threshold values of the acoustic responselevel and cumulative acoustic response dose may depend on otherparameters associated with an ultrasound treatment protocol, sonicationpattern (e.g., the frequency, duty cycle, focusing shape, and/orsonication profile varying with time) and/or history of the acousticand/or tissue response during the current or previous treatments. Forexample, lower threshold values may be used for ultrasound pulses thathave a higher duty cycle; this is because the target/non-target tissuemay have less time to relax between consecutive pulses. In someembodiments, larger threshold values are tolerable at the beginning ofthe treatment but smaller thresholds are preferred after, for example,the occurrence of a major therapeutic event during the treatment.

In various embodiments, operation of the transducer elements 104 (suchas activation, deactivation or adjustment of the sonication pattern)and/or the administration system 124 is determined based on a tissueresponse dose. The tissue response dose may be based on the maximumclinically tolerable temperature for each affected target/non-targetregion based on the types, properties and/or other anatomicalcharacteristics of the tissue in each region. Thus, various type oftissue having different properties at different locations may havedifferent tissue response doses. The tissue response dose may beobtained using any suitable approach prior to and/or during treatment.For example, referring to FIG. 5A, the tissue response dose may beempirically correlated to the acoustic response level and/or cumulativeacoustic response dose; accordingly, the tissue response dose may beacquired based on the acoustic response level and/or cumulative acousticresponse dose detected/computed as described above.

Additionally or alternatively, the tissue response dose may bedetermined using the imager (e.g., an MRI device) 112. For example, theMRI device 112 may measure the disrupted area of the target BBB region204 and/or its surrounding region 206 resulting from the microbubblecavitation in real time. The size of the disrupted area may correlate tothe tissue response dose as shown in FIG. 5B. In various embodiments,the temperature at the target BBB region and/or it surrounding regionrepresents the tissue response dose thereof. The temperature dependenceof MRI T₂ relaxation times in the target BBB region 204 and itssurrounding region 206 may be determined prior to the ultrasoundprocedure. During the ultrasound procedure, the MRI T₂ relaxation timecan be measured quickly (within 1 ms to 1 sec) in order to estimate thetemperature of the target BBB region 204 and/or it surrounding region206 in real time. This approach advantageously provides real-timetemperature feedback to the ultrasound controller 108 which may adjustthe ultrasound transmission accordingly. For example, if the measuredtemperature is below the predetermined maximum temperature, theultrasound procedure may continue to induce more microbubble cavitationto disrupt the target BBB region 204 by, for example, transmittingadditional pulses, increasing the amplitudes and/or duty cycles of thepulses. If, however, the measured temperature is above the maximumtemperature, the ultrasound procedure may be halted to avoid permanentlydamaging the tissue. It should be noted that other MRI signals may beadditionally or alternatively used to estimate the tissue response ofthe target BBB region 204 and/or it surrounding region 206. For example,MRI T₂* weighted imaging may advantageously detect an extravasation(level) of the blood in the brain. In addition, temperature-sensitive MRparameters, such as the proton resonance frequency (PRF), the diffusioncoefficient (D), T₁ and T₂ relaxation times, magnetization transfer,and/or the proton density, as well as temperature-sensitive contrastagents, may be utilized alone or in combination to estimate the tissueresponse.

FIG. 6 illustrates a representative approach 600 to using ultrasoundsonication to induce microbubble cavitation for temporarily disrupting apatient's BBB in a controlled and reversible manner. In a first step602, an imager (e.g., an MRI device) is utilized to acquire anatomicalcharacteristics of various regions of the patient's BBB and itssurrounding tissue prior to applying the ultrasound sonication. In asecond step 604, threshold values of an acoustic response level and acumulative acoustic response dose associated with the microbubbles ateach one of the target BBB regions and/or its surrounding region(s), andthreshold tissue response dose(s) associated with the target BBBregion(s) and/or its surrounding region(s) may be determined based onthe anatomical characteristics of the tissue extracted from the MRI dataas described above. Different types of the target/non-target tissue atdifferent locations may have different threshold values. The thresholdvalues of the acoustic response level and cumulative acoustic responsedose and the threshold tissue response dose(s) may then be stored in adatabase in memory that can be accessed by the controller 108. In athird step 606, microbubbles are generated by application of theultrasound pulses and/or introduced by an administration system near thetarget BBB region. In a fourth step 608, the ultrasound transducer arraymay be activated to apply waves or pulses so as to induce microbubblecavitation near the target BBB region. In a fifth step 610, acousticsignals from the microbubbles may be continuously measured (e.g., afterdelivery of each sonication) and compared to the predetermined thresholdvalues of the acoustic response level and/or cumulative acousticresponse dose. If the amplitudes of the detected acoustic signals areabove the threshold values, the magnitude and/or amount of microbubblecavitation may exceed a safe (i.e., clinically tolerable) level;therefore, the ultrasound procedure may be suspended until the detectedacoustic signal amplitudes fall below the threshold values or after arecovery interval following application of the maximum tolerable dose(in a sixth step 612).

If the acoustic response level and/or cumulative acoustic response doseare below the respective threshold values, more microbubbles may begenerated and/or introduced to increase cavitation events to continuedisruption of the target BBB region (in a seventh step 614).Additionally or alternatively, the ultrasound transducer may beactivated to deliver the next wave/pulse with the same or differentamplitude and sonication pattern from the previous applied waves/pulses(in an eighth step 616). In addition, during the ultrasound procedure,the imager (e.g., MRI device) may measure the temperature of the targetBBB region and/or its surrounding region in real time (in a ninth step618). For example, the real-time temperature may be acquired bymeasuring the MRI T₂ relaxation time. Again, if the measured temperatureis below the predetermined threshold of the tissue response dose,additional microbubbles may be generated and/or introduced (step 614)and/or the ultrasound procedure may continue (step 616). If, however,the measured temperature is above the threshold, the ultrasoundprocedure is halted to avoid overheating which may result in permanentdamage to the target BBB region and/or its surrounding region (step612). In one embodiment, the database may alternatively or additionallystore threshold values associated with other temperature sensitive MRparameters, such as the PRF, diffusion coefficient (D), T₁ relaxationtime, magnetization transfer, proton density, as well as parametersassociated with the temperature sensitive contrast agents. The imagermay then measure these parameters during the ultrasound procedure; themeasured values may then be compared against the stored threshold valuesand, based thereon, the controller 108 may operate the transducer array102 and/or administrative system as described above.

In some embodiments, the MRI device also acquires anatomic images of thetarget BBB region and/or its surrounding region during the ultrasoundprocedure (in a tenth step 620). If an undesired change in the targetBBB region and/or its surrounding region is observed, the ultrasoundprocedure may be stopped immediately. The undesired change may include,for example, the size of the disrupted BBB area being larger than thedesired area and/or a portion of the non-target surrounding region beingdisrupted. Embodiments of the present invention thus employ a cavitationdetection device (or an ultrasound transducer array) and an imagingdevice to monitor formation/generation of the microbubbles, thecavitation events, and tissue response in real-time during an ultrasoundprocedure; based on the monitored response, disruption of the target BBBregion may then be facilitated in a controlled manner withoutpermanently damaging the target BBB region and/or its surroundingregion.

Thereafter, a therapeutic agent may penetrate from the bloodstream tothe targeted brain cells via the opened BBB region. The therapeuticagent may include any drug that is suitable for treating a brain tumor.For example, for treating glioblastoma (GBM), the drug may include orconsist of, e.g., one or more of Busulfan, Thiotepa, CCNU (lomustine),BCNU (carmustine), ACNU (nimustine), Temozolomide, Methotrexate,Topotecan, Cisplatin, Etoposide, Irinotecan/SN-38, Carboplatin,Doxorubicin, Vinblastine, Vincristine, Procarbazine, Paclitaxel,Fotemustine, Ifosfamide/4-Hydroxyifosfamide/aldoifosfamide, Bevacizumab,5-Fluorouracil, Bleomycin, Hydroxyurea, Docetaxel, Cytarabine (cytosinearabinoside, ara-C) /ara-U, etc.

Those skilled in the art can select a drug and a BBB opening regimeoptimized to enhance drug absorption across the BBB within patientsafety constraints. In this regard, it is known that the BBB is actuallyalready disrupted in the core of many tumors, allowing partialpenetration of antitumor drugs; but the BBB is widely intact around the“brain adjacent to tumor” (BAT) region where invasive/escaping GBM cellscan be found, and which cause tumor recurrence. Overcoming the BBB forbetter drug delivery within the tumor core and the BAT can beaccomplished using ultrasound as described herein. The drugs employedhave various degrees of toxicity and various penetration percentagesthrough the BBB. An ideal drug has high cytotoxicity to the tumor and noBBB penetration (so that its absorption and cytotoxic effects can beconfined to regions where the BBB is disrupted), low neurotoxicity (toavoid damage to the nervous system), and tolerable systemic toxicity(e.g., below a threshold) at the prescribed doses. The drug may beadministered intravenously or, in some cases, by injection proximate tothe tumor region.

Functionality for performing disruption of a target BBB region in acontrolled and reversible manner as described above, whether integratedwithin the controller 108 of the ultrasound system 100, the imager 122and/or the administration system 124 or provided by a separate externalcontroller, may be structured in one or more modules implemented inhardware, software, or a combination of both. In addition, the imager122 and/or the administration system 124 may be controlled by thecontroller 108 or other separate processor(s). For embodiments in whichthe functions are provided as one or more software programs, theprograms may be written in any of a number of high level languages suchas PYTHON, FORTRAN, PASCAL, JAVA, C, C++, C#, BASIC, various scriptinglanguages, and/or HTML. Additionally, the software can be implemented inan assembly language directed to the microprocessor resident on a targetcomputer; for example, the software may be implemented in Intel 80x86assembly language if it is configured to run on an IBM PC or PC clone.The software may be embodied on an article of manufacture including, butnot limited to, a floppy disk, a jump drive, a hard disk, an opticaldisk, a magnetic tape, a PROM, an EPROM, EEPROM, field-programmable gatearray, or CD-ROM. Embodiments using hardware circuitry may beimplemented using, for example, one or more FPGA, CPLD or ASICprocessors.

The terms and expressions employed herein are used as terms andexpressions of description and not of limitation, and there is nointention, in the use of such terms and expressions, of excluding anyequivalents of the features shown and described or portions thereof. Inaddition, having described certain embodiments of the invention, it willbe apparent to those of ordinary skill in the art that other embodimentsincorporating the concepts disclosed herein may be used withoutdeparting from the spirit and scope of the invention. Accordingly, thedescribed embodiments are to be considered in all respects as onlyillustrative and not restrictive.

What is claimed is:
 1. A system for temporarily disrupting a patient'sblood-brain barrier (BBB), the system comprising: an ultrasoundtransducer; and a controller configured to: (a) store at least one ofthreshold values of an acoustic response level, a cumulative acousticresponse dose, and a tissue response dose associated with at least onetarget BBB region and its surrounding regions; (b) cause the transducerto transmit at least one ultrasound pulse; (c) acquire at least one ofthe acoustic response level, the acoustic response dose, or the tissueresponse dose associated with at least one of the target BBB region orits surrounding regions; (d) compare the measurement with acorresponding stored threshold value; and (e) operate the transducerbased at least in part on the comparison.
 2. The system of claim 1,wherein the controller is further configured to: cause at least one of adetection device or the transducer to measure acoustic signals from thetarget BBB region and/or its surrounding regions; and determine theacoustic response level, the acoustic response dose, and/or the tissueresponse dose based at least in part on the measured acoustic signals.3. The system of claim 2, further comprising a filter for filtering themeasured acoustic signals from the target BBB region and/or itssurrounding regions.
 4. The system of claim 3, wherein the filter isconfigured to select at least one of a harmonic or a sub-harmonicresponse to the transmitted ultrasound pulse.
 5. The system of claim 3,wherein the filter is configured to select a broadband response to thetransmitted ultrasound pulse.
 6. The system of claim 1, wherein thecontroller is further configured to compute the acoustic response doseby integrating the acoustic response level over a predetermined timeperiod.
 7. The system of claim 1, wherein the controller is furtherconfigured to cause generation of microbubbles in the at least one ofthe target BBB region or its surrounding regions using the transducer.8. The system of claim 1, further comprising an administration devicefor introducing microbubbles into the at least one of the target BBBregion or its surrounding regions.
 9. The system of claim 1, furthercomprising an administration device for introducing a seed microbubbleinto the at least one of the target BBB region or its surroundingregions, wherein the controller is further configured to causegeneration of additional microbubbles using the seed microbubble and thetransducer.
 10. The system of claim 1, wherein the controller is furtherconfigured to determine the threshold values of the acoustic responselevel, the cumulative acoustic response dose and the tissue responsedose associated with the at least one target BBB region and itssurrounding regions based at least in part on anatomical characteristicsthereof.
 11. The system of claim 10, wherein there are a plurality oftarget BBB regions and the controller is further configured to determineand store the threshold values of the acoustic response level, thecumulative acoustic response dose and the tissue response doseassociated with each of the target BBB regions and each of theirsurrounding regions.
 12. The system of claim 10, wherein the at leastone of threshold values of the acoustic response level, the cumulativeacoustic response dose and the tissue response dose associated with theat least one target BBB region are different from the threshold valuesof the acoustic response level, the cumulative acoustic response doseand the tissue response dose associated with the surrounding regions.13. The system of claim 10, wherein the surrounding regions comprisetissue having different types at different locations, and the controlleris further configured to determine the threshold values of the acousticresponse level, the cumulative acoustic response dose and the tissueresponse dose associated with each type of the tissue at each locationof the surrounding regions.
 14. The system of claim 10, furthercomprising an imaging device for acquiring the anatomicalcharacteristics of the target BBB region and its surrounding regions.15. The system of claim 14, wherein the image device further acquiresimages of the target BBB region and/or its surrounding regions and thecontroller is further configured to determine the tissue response dosebased at least in part on the acquired images.
 16. The system of claim1, wherein the tissue response dose comprises a temperature associatedwith the at least one of the target BBB region and its surroundingregions.
 17. The system of claim 1, wherein the tissue response dose isacquired by measuring an MRI T₂ relaxation time associated with the atleast one of the target BBB region or its surrounding regions.
 18. Thesystem of claim 1, wherein the controller is further configured to:determine whether the at least one of the acoustic response level, theacoustic response dose, or the tissue response dose exceeds thecorresponding threshold value; and if so, suspend ultrasound sonication,and if not, cause the transducer to transmit a second ultrasound pulse.19. The system of claim 1, wherein the tissue response dose comprisesinformation derived from at least one of MRI T₂* imaging or MRI T₂*weighted imaging associated with the at least one of the target BBBregion or its surrounding regions.
 20. The system of claim 1, whereinthe controller is further configured to operate the transducer byadjusting at least one of a transmitting power or a sonication patternassociated with the transducer. 21-42. (canceled)